Enamine activation first approaches

Scheme 2.2 First approaches toward the enamine activation concept.

The problems involved are exemplified here by Knorr s pyrrole synthesis (A. Gossauer, 1974). It has been known for almost a century that a-aminoketones (C2N components) react with 1,3-dioxo compounds (C2 components) to form pyrroles (C4N-heterocycles). A side-reaction is the cyclodimerization of the a-aminoketones to yield dihydropyrazines (C4Nj), but this can be minimized by keeping the concentration of the ar-aminoketone low relative to the 1,3-dioxo compound. The first step in Knorr s pyrrole synthesis is the formation of an imine. This depends critically on the pH of the solution. The nucleophilicity of the amine is lost on protonation, whereas the carbonyl groups are activated by protons. An optimum is found around pH 5, where yields of about 60% can be reached. At pH 4 or 6 the yield of the pyrrole may approach zero. The ester groups of /7-keto esters do not react with the amine under these conditions. If a more reactive 1,3-diketone is used, it has to be symmetrical, otherwise mixtures of two different imines are obtained. The imine formed rearranges to an enamine, which cyclizes and dehydrates to yield a 3-acylpyrrole as the normal Knorr product (A. Gossauer, 1974 G.W. Kenner, 1973 B). 

While several metal-catalysed approaches to solve the task of generating fl tz-l,2-diols have been developed, this method remains remarkable, since it represents the first small molecule-catalysed, catalytic version of this transformation. The starting materials do not need activation or protection, and the reaction can be performed under standard conditions without further precautions. The selectivity of the reaction potentially results from a hydro Q acetone enamine-initiated transition state (5). More recently, Enders et al. applied a related method to the organocatalytic synthesis of sialic acid precursors (Scheme 5.6). Protected pyruvic aldehyde (6) was reacted with several aldehydes, forming the desired aldols (7) in moderate yields, but good selectivities (31-51%, 90-92% de, 73-99% ee). The conditions were optimised to limit detrimental side reaetions sueh as Mannich elimination or formation of the aeetal self-aldolisation produet. While generally easily applicable and robust, the method laeks effieiency in one key parameter, its reaction time. This limitation, combined with moderate yields unfortunately prevents a scale-up to or beyond the pilot plant. 

In this mechanism, the imine I is firstly formed between benzaldehyde and the urea A. The imine I is further activated through hydrogen bonds with the protonated quinuclidine backbone of catalyst 45. This activation helps to approach the imine I closer to the reaction center of the enamine n... 

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